Dibenzylsulfamides



United States Patent Ofifice 3,318,952 Patented May 9,1967

3,318,952 DIBENZYLSULFAMIDES William J. Houlihan, Mountain Lakes, N.J.,assignor to Sandoz Inc., Hanover, NJ.

No Drawing. Filed Dec. 8, 1964, Ser. No. 416,907 Claims. (Cl. 260--556)This is a continuation-in-part of application Ser. No. 339,354 filed onJan. 22, 1964, now abandoned.

The present invention is directed to dibenzylsulfamides la 1 whereineach of R R R R R R, R", and R is either a hydrogen atom (-H) or one ofthe following functional groups: lower alkyl, preferably having from 1to 5 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl andamyl; lower alkoxy, preferably having from 1 to 5 carbon atoms, e.g.methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy;di(lower)alkylamino,.each alkyl of which preferably having from 1 to 5carbon atoms, e.g. dimethylamino and N-methyl-N-ethylamino; aziridyl;pyrrolidyl; piperidyl; homopiperidyl; a fluorine atom (-F); a chlorineatom (-Cl); a bromine atom (Br); trifiuoromethyl (CF with the provisothat a plurality of trifluoromethyl groups are not ortho to each other;and, together with the functional ,group on the adjacent ring carbonatom, methylenedioxy (OCH O). 3 r

An object of this invention is to obtain compounds which are useful asanticonvulsants. A further object is .to obtain anticonvulsants directlyfrom starting materials a which are either readily available or preparedfrom readily available compounds by methods well known to the art.Additional objects are apparent from the description which follows.

The preparation of compounds I is accomplished by heating at atemperature within the range of from about to about 250 C. and in atertiary amine (a) a dibenzylamine II and (b) sulfamide III:

A reaction temperature in excess of 50 C. is recommended, and apreferred range is from about to about 125 C. Agitation may be employedduring the reaction, but none is required. j

The tertiary amine medium provides a solvent system in which thereaction takes place. Contemplated tertiary amines include, for example,tri(lower)alkylarnines, e.g. triethylamine; aryldi(lower)alkylamines,e.g. phenyldimethylarnine; (lower)alkyl pyrroles, e.g. N-propyl-pyrrole;pyridine; (lower)alkyl pyridines, e.g. 3-ethyl pyridine; (lower)alkoxypyridines, e.g. 2,5-dimethoxypyridine; quinoline; (lower) alkylquinolines, e.g. S-ethyl-quinolines; (lower)alkoxy quinolines, e.g.3,6-dimethoxy-quinoline; N-(1ower)a1kyl morpholine, e.g.N-methyl-morpholine; and N,N-di(lower)alkyl piperazine, e.g. N-methyl-N-ethyl-piperazine. I

The temperature at which reaction A is conducted is usually the refluxtemperature of the system.

Except for the title compound of Example 1, compounds I areanticonvulsants and antidepressants which may be administered eitherorally or parenterally. They are useful, for example, in the therapy ofconvulsive seizures. Average daily doses vary, but may be between 200milligrams and 350 milligrams.

Each of the pharmaceutically active compounds of this invention may be,e.g., incorporated, for oral administration, in a tablet as the soleactive ingredient. A typical tablet is constituted by from 1 to 3percent binder, e.g. tragacanth; from 3 to 10 percent disintegratingagent, e.g. corn starch; from 2 to 10 percent'lubricant, e.g. talcum;from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an averagedosage of active ingredient; and q.s. 100 percent of filler, e.g.lactose; all percentages being by weight. Tablets are prepared accordingto standard tabletting techniques, which are well-known in the art,employing the necessary amounts of conventional granulating liquids,e.g. alcohol SD-30 and purified water. An exemplary tablettingformulation for the instant active compounds is:

Parts Title compound of Example 2 50 Tragacanth 2 Lactose 39.5

i Corn starch 5 Talcum I 3 Magnesium stearate 0.5

Alcohol SD-30 and purified water, q.s.

,The title compound of Example 1, as other compounds 2 I, possesses CNS(central nervous system) activity. However, said title compound hasstrong stimulant activity and is not anticonvulsant. It can beadministered either orally or parenterally in daily doses of from 35milligrams to 42 milligrams. The oral dosage form can be a tabletcomparable to that heretofore exemplified.

Similar stimulant activity, but to a reduced degree, is found in suchcompounds as N,N-dibenzyl-N,N-'dimethylsulfamide. V

The following examples illustrate the invention, all temperatures beingin degrees centigrade,.the parts and percentages being by weight unlessotherwise stated, and the relationship between parts by weight and partsby volume being the same as that between the kilogram and the liter:

EXAMPLE 1 N,N-dibenzylsulfamide In a flask equipped with a stirrer and acondenser attached to a bubble detector dissolve 2157 parts 0.11 mole)of dibenzylamine and 9.6 parts (0.10 mole) of n the following tableresults in the preparation of the :orresponding compound I.

4. EXAMPLE 3 N benzy l-N -2,4-dichlorobenzy lsul fwmid e In a flaskequipped with a stirrer and a condenser attached to a bubble detectordissolve 13.2 parts (0.05

R R l R 4 R4 i R i R R R Me -H -H -11 Me H -11 H -H Et F H -H Et F -11CF; -H -Pr -01 CF; H Pr -01 H Br Br H H Br Br H -01 -H Et F -01 H Et -FH OF3 H CFa H CFa H CFa -Me H H H Et F -H CF; H Pr Ol Br CFa OEt iPr BuF H OiPr OPr Am H H -11 OBu -0F Br F H OAm H H -01 O-CHzO- -11 -01-0'-0H20- -11 -Br Br H -01 -H Et; CF3 OMe CFa H H CFa H CFQ EXAMPLE 2mole) of N-benzy1-N-2,4-dichl-orobenzylamine and 7.0 N ben l N 34dichlorobenz [Sal amide parts (0.07 mole) of sulfamide in 40 parts byvo1um e U y f of pyridine. Stir and reflux the resulting solution untilgassing is no longer detected in the bubble detector. Remove the solventin vacuo on a rotary evaporator. Crys- 3 tallize the viscous residuefrom methanol/water. There NSOaNHz 35 are thus obtained 5.2 parts oftitle compound, M.P. 95.5"

In a flask equipped with a stirrer and a condenser attached to a bubbledetector dissolve 13.2 parts (0.05

Replacing the Nbenzyl-N-2,4-dichlorobenzylamine with an equivalentamount of each of the compounds II represented by substituents in thefollowing table results in mole) of N-benzyl-N-3,4-dichlorobenzylamineand 7.0 the preparation of the corresponding compound I.

l R1 R, 3 R4 R5 IN E R8 CF3 OMe -0F3 H H -0F3 OMe ora H Br r H Br Br H-11 -01 O-OHz-O- -o-oH2-o- 01 H -01 -.o-0H,-0 F Et H -01 N (Me) Et H lHO H Py H -Ho H parts (0.07 mole) of sulfamide in 100 parts by volumeEXAMPLE 4 of pyridine. Stir and reflux the resulting solution until 2 hgassing is no longer detected in the bubble detector. Rel w lorobenzyl)sulfamlde move the solvent in vacuo on a rotary evaporator. Crystallizethe viscous residue from methanol/water. There CH are thus obtained 4.9parts of title compound, M.P. to 9 6O III-SOr-NH:

Replacing the N-benzyl-N-3,4-dichlorobenzy1amine with 01 CH, anequivalent amount of each of the compounds II represented bysubstituents in the following table results in 01 the preparation of thecorresponding compound I. In a flask equipped with a stirrer and acondenser at- R1 R R R4 R5 R R7 I R8 Br -01? OEt iPr -N(Me)a -H -H Az BuF H OiPr -H H Py H OPr Am -11 H -11 Pi -0-0H -0- -11 OBu -01 Br HoN(Pr)Bu Az -11 -F H OAm H Az Iy H -Pr H 01 -0-0 E -o- -Pi OMe N(Et)Am Ho-H -Az -11 -01 -H H -11 H Py H -OGH -O H H H -11 CF' H P1 H H H H Htached to a bubble detector dissolve 36.6 parts (0.11 mole) ofbis-2,4-dichlorobenzylamine and 9.6 parts (0.10 mole) 6 What is claimedis: 1. A compound of the formula of sulfamide in 40 parts by volume ofpyridine. Stir and R R reflux the resulting solution until gassing is nolonger de- I I tected in the bubble detector. Remove the solvent in 5 RCH: vacuo on a rotary evaporator. Crystallize the viscous I residue frommethanol/water. The title compound is R H thus obtained. H V

Replacing the bis-2,4-dichlorobenzylamine with an I l I equivalentamount of each of the compounds 11 repre- BL- sented by substituents inthe following table results in I the preparation of the correspondingcompound I. R7 R R1 R2 R1 R4 R5 I R6 R1 Rs I In the preceding tablesabbreviations, in addition to standard elementalsymbols, were employedas follows:

Arn-amyl Az-aziridyl Bubutyl Etethyl iPrisopropyl Ho-homopiperidylMe-methyl Pi-piperidyl Prpropy1 Py-pyrrolidyl Compounds II are eitherknown or are prepared by known procedures from available compounds.Various changes can be made in compounds I without departing from thespirit or scope of the present invention or sacrificing its materialadvantages, the compounds hereinbefore described being merelyillustrative embodiments of the invention.

No references cited.

WALTER A. MODANCE, Primary Examiner. JOHN D. RANDOLPH, Examiner.

HARRY MOATZ, Assistant Examiner.

1. A COMPOUND OF THE FORMULA